{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T01:04:26Z","timestamp":1782176666084,"version":"3.54.5"},"reference-count":65,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nihon University Research Grant for emerging infectious diseases"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Bacteraemia brought on by Clostridium perfringens has a very low incidence but is severe and fatal in fifty per cent of cases. C. perfringens is a commensal anaerobic bacterium found in the environment and in the intestinal tracts of animals; it is known to produce six major toxins: \u03b1-toxin, \u03b2-toxin, \u03b5-toxin, and others. C. perfringens is classified into seven types, A, B, C, D, E, F and G, according to its ability to produce \u03b1-toxin, enterotoxin, and necrotising enterotoxin. The bacterial isolates from humans include types A and F, which cause gas gangrene, hepatobiliary infection, and sepsis; massive intravascular haemolysis (MIH) occurs in 7\u201315% of C. perfringens bacteraemia cases, resulting in a rapid progression to death. We treated six patients with MIH at a single centre in Japan; however, unfortunately, they all passed away. From a clinical perspective, MIH patients tended to be younger and were more frequently male; however, there was no difference in the toxin type or genes of the bacterial isolates. In MIH cases, the level of \u03b8-toxin in the culture supernatant of clinical isolates was proportional to the production of inflammatory cytokines in the peripheral blood, suggesting the occurrence of an intense cytokine storm. Severe and systemic haemolysis is considered an evolutionary maladaptation as it leads to the host\u2019s death before the bacterium obtains the benefit of iron utilisation from erythrocytes. The disease\u2019s extraordinarily quick progression and dismal prognosis necessitate a straightforward and expedient diagnosis and treatment. However, a reliable standard of diagnosis and treatment has yet to be put forward due to the lack of sufficient case analysis.<\/jats:p>","DOI":"10.3390\/microorganisms11040824","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T04:31:05Z","timestamp":1679632265000},"page":"824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Clinical and Microbiological Features of Fulminant Haemolysis Caused by Clostridium perfringens Bacteraemia: Unknown Pathogenesis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1912-6845","authenticated-orcid":false,"given":"Ai","family":"Suzaki","sequence":"first","affiliation":[{"name":"Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Ohyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1022-1443","authenticated-orcid":false,"given":"Satoshi","family":"Hayakawa","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Ohyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.3201\/eid2707.203471","article-title":"Non-C. difficile Clostridioides bacteremia in intensive care patients, France","volume":"27","author":"Morel","year":"2021","journal-title":"Emerg. Infect. Dis."},{"key":"ref_2","first-page":"343","article-title":"Clostridium perfringens septicaemia with massive intravascular haemolysis: A case report and review of the literature","volume":"68","author":"Bomers","year":"2010","journal-title":"Neth. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1177\/0885066613498043","article-title":"Massive intravascular hemolysis from Clostridium perfringens septicemia: A review","volume":"29","author":"Simon","year":"2014","journal-title":"J. Intensive Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1007\/s12185-020-03060-z","article-title":"Clostridium perfringens sepsis in three patients with acute leukemia and review of the literature","volume":"113","author":"Liu","year":"2021","journal-title":"Int. J. Hematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1007\/s11739-022-03036-3","article-title":"Massive intravascular hemolysis is an important factor in Clostridium perfringens-induced bacteremia","volume":"17","author":"Suzaki","year":"2022","journal-title":"Intern. Emerg. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.ijid.2021.12.331","article-title":"Toxinotype A Clostridium perfringens causing septicaemia with intravascular haemolysis: Two cases and review of the literature","volume":"115","author":"Woittiez","year":"2022","journal-title":"Int. J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s13054-020-02950-2","article-title":"Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019-results from a systematic review and meta-analysis","volume":"24","author":"Bauer","year":"2020","journal-title":"Crit. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.cmi.2019.10.031","article-title":"Burden of bacterial bloodstream infection-a brief update on epidemiology and significance of multidrug-resistant pathogens","volume":"26","author":"Kern","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1016\/j.ajog.2013.09.045","article-title":"Clostridium perfringens sepsis following a molar pregnancy","volume":"210","author":"Adams","year":"2014","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41426-018-0144-8","article-title":"An update on the human and animal enteric pathogen Clostridium perfringens","volume":"7","author":"Kiu","year":"2018","journal-title":"Emerg. Microbes Infect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"361","DOI":"10.2217\/fmb.13.168","article-title":"Towards an understanding of the role of Clostridium perfringens toxins in human and animal disease","volume":"9","author":"Uzal","year":"2014","journal-title":"Future Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1086\/321883","article-title":"Clinical features of clostridial bacteremia: A review from a rural area","volume":"33","author":"Rechner","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102202","DOI":"10.1016\/j.anaerobe.2020.102202","article-title":"Clinical relevance of Clostridium bacteremia: An 8-year retrospective study","volume":"63","author":"Stabler","year":"2020","journal-title":"Anaerobe"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.jinf.2008.06.018","article-title":"Epidemiology of Clostridium species bacteremia in Calgary, Canada, 2000\u20132006","volume":"57","author":"Leal","year":"2008","journal-title":"J. Infect."},{"key":"ref_15","first-page":"20","article-title":"Sepsis and immunosenescence in the elderly patient: A review","volume":"4","author":"Aldecoa","year":"2017","journal-title":"Front. Med."},{"key":"ref_16","first-page":"2599","article-title":"Hemolytic anemia","volume":"69","author":"Dhaliwal","year":"2004","journal-title":"Am. Fam. Phys."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1002\/jca.21586","article-title":"Therapeutic plasma exchange in the treatment of complicated Plasmodium falciparum malaria: A case report","volume":"33","author":"Ou","year":"2018","journal-title":"J. Clin. Apher."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1309\/N3DP9MFPNUJD4XJY","article-title":"Babesiosis: Two atypical cases from Minnesota and a review","volume":"120","author":"Setty","year":"2003","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1093\/cid\/ciz042","article-title":"48-year-old male with febrile neutropenia and massive hemolysis","volume":"69","author":"Jakharia","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e955","DOI":"10.1016\/j.ijid.2013.03.001","article-title":"Clinical significance and outcomes of Clostridium perfringens bacteremia\u2014A 10-year experience at a tertiary care hospital","volume":"17","author":"Yang","year":"2013","journal-title":"Int. J. Infect. Dis."},{"key":"ref_21","first-page":"569","article-title":"Epidemiological and pathobiological profiles of Clostridium perfringens infections: Review of consecutive series of 33 cases over a 13-year period","volume":"8","author":"Shindo","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1080\/00365540050164173","article-title":"Clostridial bacteremia in the community hospital","volume":"32","author":"Haddy","year":"2000","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sakaue, M., Ota, K., Nakamura, E., Nitta, M., Oka, M., Oishi, Y., Sano, Y., Yonogi, S., and Takasu, A. (2019). Type A fuluminant Clostridium perfringens sepsis indicated RBC\/Hb discrepancy; a case report. BMC Infect. Dis., 19.","DOI":"10.1186\/s12879-019-4350-3"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"219","DOI":"10.12659\/AJCR.895721","article-title":"Clostridium perfringens infection in a febrile patient with severe hemolytic anemia","volume":"17","author":"Hashiba","year":"2016","journal-title":"Am. J. Case Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4278904","DOI":"10.1155\/2018\/4278904","article-title":"Clostridium perfringens septicemia and a bleeding ulcer of a jejunal interposition: A case report and short review of the literature","volume":"2018","author":"Wild","year":"2018","journal-title":"Case Rep. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"713509","DOI":"10.3389\/fmicb.2021.713509","article-title":"Pathogenic characterization of Clostridium perfringens strains isolated from patients with massive intravascular hemolysis","volume":"12","author":"Suzaki","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.anaerobe.2009.10.003","article-title":"Identification of a two-component VirR\/VirS regulon in Clostridium perfringens","volume":"16","author":"Ohtani","year":"2010","journal-title":"Anaerobe"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.anaerobe.2014.05.014","article-title":"Clostridial pore-forming toxins: Powerful virulence factors","volume":"30","author":"Popoff","year":"2014","journal-title":"Anaerobe"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1574-695X.1993.tb00414.x","article-title":"Clostridium perfringens invasiveness is enhanced by effects of theta toxin upon PMNL structure and function: The roles of leukocytotoxicity and expression of CD11\/CD18 adherence glycoprotein","volume":"7","author":"Bryant","year":"1993","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7904","DOI":"10.1128\/IAI.69.12.7904-7910.2001","article-title":"Synergistic effects of \u03b1-toxin and perfringolysin O in Clostridium perfringens-mediated gas gangrene","volume":"69","author":"Awad","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.3390\/toxins7051702","article-title":"Perfringolysin O: The underrated Clostridium perfringens toxin?","volume":"7","author":"Verherstraeten","year":"2015","journal-title":"Toxins"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/1297-9716-44-45","article-title":"The synergistic necrohemorrhagic action of Clostridium perfringens perfringolysin and alpha toxin in the bovine intestine and against bovine endothelial cells","volume":"44","author":"Verherstraeten","year":"2013","journal-title":"Vet. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2020185","DOI":"10.4322\/acr.2020.185","article-title":"Sudden death caused by Clostridium perfringens sepsis presenting as massive intravascular hemolysis","volume":"10","author":"Chinen","year":"2020","journal-title":"Autops. Case Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1093\/intimm\/dxu081","article-title":"Therapeutic uses of anti-interleukin-6 receptor antibody","volume":"27","author":"Kang","year":"2014","journal-title":"Int. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1016\/j.forsciint.2015.05.014","article-title":"Fatal Clostridium perfringens septicemia suggested by postmortem computed tomography: A medico-legal autopsy case report","volume":"253","author":"Yamaguchi","year":"2015","journal-title":"Forensic Sci. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1378\/chest.09-0950","article-title":"A 61-year-old-man with massive intravascular hemolysis","volume":"136","author":"Uppal","year":"2009","journal-title":"Chest"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3109\/08830185.2014.889129","article-title":"The role of the liver in sepsis","volume":"33","author":"Yan","year":"2014","journal-title":"Int. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"547","DOI":"10.17219\/acem\/68363","article-title":"Liver dysfunction in sepsis","volume":"27","author":"Inglot","year":"2018","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_39","first-page":"310","article-title":"Clostridium perfringens liver abscess with massive haemolysis","volume":"16","author":"Ng","year":"2010","journal-title":"Hong Kong Med. J."},{"key":"ref_40","first-page":"948071","article-title":"Acute hemolysis in the emergency department: Think about Clostridium perfringens!","volume":"2013","author":"Baptiste","year":"2013","journal-title":"Case Rep. Emerg. Med."},{"key":"ref_41","first-page":"357","article-title":"Massive intravascular hemolysis in a patient infected by Clostridium perfringens","volume":"60","author":"Ohtani","year":"2006","journal-title":"Acta. Med. Okayama"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1200\/JCO.2005.03.4009","article-title":"Intravascular hemolysis as a complication of Clostridium perfringens sepsis","volume":"24","author":"McArthur","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"107087","DOI":"10.1016\/j.intimp.2020.107087","article-title":"Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets","volume":"89","author":"Kumar","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1093\/infdis\/165.5.879","article-title":"Streptococcal toxic shock syndrome: Synthesis of tumor necrosis factor and interleukin-1 by monocytes stimulated with pyrogenic exotoxin A and streptolysin O","volume":"165","author":"Hackett","year":"1992","journal-title":"J. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1172\/JCI111334","article-title":"Induction of human interleukin-1 by a product of Staphylococcus aureus associated with toxic shock syndrome","volume":"73","author":"Ikejima","year":"1984","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.anaerobe.2016.03.011","article-title":"Fatal Clostridium perfringens sepsis due to emphysematous gastritis and literature review","volume":"40","author":"Sarvari","year":"2016","journal-title":"Anaerobe"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1474-9728.2004.00102.x","article-title":"Innate immunity in aging: Impact on macrophage funcion","volume":"3","author":"Plowden","year":"2004","journal-title":"Aging Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/AIA.0b013e318034194e","article-title":"Cytokines, infammation, and pain","volume":"45","author":"Zhang","year":"2007","journal-title":"Int. Anesthesiol. Clin."},{"key":"ref_49","first-page":"287","article-title":"Mechanism of IL-8-induced acute lung injury through pulmonary surfactant proteins A and B","volume":"19","author":"Yang","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1186\/s13054-016-1470-7","article-title":"Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury","volume":"20","author":"Aisiku","year":"2016","journal-title":"Crit. Care"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"591","DOI":"10.2169\/internalmedicine.3793-19","article-title":"Clostridium perfringens septicemia with massive intravascular hemolysis","volume":"59","author":"Fujikawa","year":"2020","journal-title":"Intern. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S173","DOI":"10.1086\/516220","article-title":"Antibody responses to clostridial infection in humans","volume":"25","author":"Johnson","year":"1997","journal-title":"Clin. Infect. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1097\/00000658-196606000-00007","article-title":"Clostridial infections of the abdominal wall: Review of 10 cases","volume":"163","author":"McSwain","year":"1966","journal-title":"Ann. Surg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s40813-019-0127-8","article-title":"Vaccination against Clostridium perfringens type C enteritis in pigs: A field study using an adapted vaccination scheme","volume":"5","author":"Richard","year":"2019","journal-title":"Porcine Health Manag."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Thapa, R., Ray, S., and Keyel, P.A. (2020). Interaction of macrophages and cholesterol-dependent cytolysins: The impact on immune response and cellular survival. Toxins, 12.","DOI":"10.3390\/toxins12090531"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1111\/bjh.17361","article-title":"Vasculo-toxic and pro-inflammatory action of unbound haemoglobin, haem and iron in transfusion-dependent patients with haemolytic anaemias","volume":"193","author":"Vinchi","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"396527","DOI":"10.1155\/2013\/396527","article-title":"Therapeutic approaches to limit hemolysis-driven endothelial dysfunction: Scavenging free heme to preserve vasculature homeostasis","volume":"2013","author":"Vinchi","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3389\/fphar.2014.00061","article-title":"Heme in pathophysiology: A matter of scavenging, metabolism and trafficking across cell membranes","volume":"5","author":"Chiabrando","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1172\/JCI26857","article-title":"Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice","volume":"116","author":"Belcher","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3389\/fphys.2015.00187","article-title":"Hemopexin and haptoglobin: Allies against heme toxicity from hemoglobin not contenders","volume":"6","author":"Smith","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1182\/blood.2021011629","article-title":"Type I interferon is induced by hemolysis and drives antibody-mediated erythrophagocytosis in sickle cell disease","volume":"138","author":"Liu","year":"2021","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1126\/science.1198469","article-title":"Induction of colonic regulatory T cells by indigenous Clostridium species","volume":"331","author":"Atarashi","year":"2011","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"25523","DOI":"10.4088\/PCC.18m02401","article-title":"Relationship between the fecal microbiota and depression and anxiety in pediatric patients with orthostatic intolerance","volume":"21","author":"Ishii","year":"2019","journal-title":"Prim. Care Companion CNS Disord."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3920\/BM2016.0216","article-title":"Gut dysbiosis following C-section instigates higher colonisation of toxigenic Clostridium perfringens in infants","volume":"8","author":"Nagpal","year":"2017","journal-title":"Benef. Microbes"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"102639","DOI":"10.1016\/j.anaerobe.2022.102639","article-title":"Prevalence, molecular characterization, and antimicrobial resistance profile of Clostridium perfringens from India: A scoping review","volume":"77","author":"Yadav","year":"2022","journal-title":"Anaerobe"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/4\/824\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:01:37Z","timestamp":1760122897000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/4\/824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,23]]},"references-count":65,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["microorganisms11040824"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms11040824","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,23]]}}}